Yamaura Shizuka, Fukao Miki, Ishida Kazuya, Taguchi Masato, Hashimoto Yukiya
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
Eur J Drug Metab Pharmacokinet. 2014 Mar;39(1):53-9. doi: 10.1007/s13318-013-0140-2. Epub 2013 Jun 6.
Heart failure is accompanied with tissue (circulatory) hypoxia, and the metabolism of several drugs has been reported to be reduced in heart failure. The aim of this study was to investigate the effect of another type of respiratory hypoxia, hypoxic hypoxia (FiO2 15 % for 24 h followed by FiO2 10 % for 9 days) on the metabolism of carvedilol enantiomers in rats. Oxidation of carvedilol in rat liver microsomes was evaluated in the presence of reduced nicotinamide adenine dinucleotide phosphate, whereas glucuronidation was evaluated in the presence of UDP-glucuronic acid. Both oxidation and glucuronidation activities for two carvedilol enantiomers in hypoxic rat liver microsomes were similar to those in control rat liver microsomes. We also performed pharmacokinetic analysis of carvedilol enantiomers following intraportal infusion in control and hypoxic rats. The mean (±S.E.) portal clearance value of R- and S-carvedilol in control rats was 72 ± 16 and 156 ± 31 ml/min/kg, respectively, whereas that of the R- and S-enantiomers in hypoxic rats was 68 ± 8 and 113 ± 14 ml/min/kg, respectively. These findings indicated that the metabolism of carvedilol enantiomers was not significantly diminished in rats with chronic hypoxic hypoxia, and that other factor(s) besides hypoxia may be responsible for the reduced drug metabolism in heart failure.
心力衰竭伴有组织（循环）缺氧，据报道，几种药物在心力衰竭时的代谢会降低。本研究的目的是探讨另一种类型的呼吸性缺氧，即低张性缺氧（先给予24小时15%的氧浓度，随后9天给予10%的氧浓度）对大鼠体内卡维地洛对映体代谢的影响。在还原型烟酰胺腺嘌呤二核苷酸磷酸存在的情况下评估大鼠肝微粒体中卡维地洛的氧化作用，而在尿苷二磷酸葡萄糖醛酸存在的情况下评估葡萄糖醛酸化作用。低氧大鼠肝微粒体中两种卡维地洛对映体的氧化和葡萄糖醛酸化活性均与对照大鼠肝微粒体中的相似。我们还对对照大鼠和低氧大鼠经门静脉注射卡维地洛对映体后的药代动力学进行了分析。对照大鼠中R-和S-卡维地洛的平均（±标准误）门静脉清除率分别为72±16和156±31 ml/min/kg，而低氧大鼠中R-和S-对映体的平均门静脉清除率分别为68±8和113±14 ml/min/kg。这些结果表明，在慢性低张性缺氧的大鼠中，卡维地洛对映体的代谢并未显著减弱，并且除缺氧外的其他因素可能是导致心力衰竭时药物代谢降低的原因。
